Approximately 70% of newly diagnosed breast cancer patients are estrogen receptor-α positive (ER+). However, almost 50% of all ER+ breast tumors will not respond to endocrine therapy. Tamoxifen produces an overall 26% proportional reduction in mortality but many ER+ tumors that show an initial response eventually recur. Resistance to endocrine therapy remains a significant clinical problem and advanced ER+ breast cancer is largely an incurable disease.
X-Box binding protein 1 (XBP1) is a key component of the signaling mechanism that contributes to endocrine resistance in breast cancer cells. XBP1 is a critical component of the unfolded protein response (UPR), which can act as a switch to control the balance between cell death and cell survival. UPR is induced by cellular stressors and is activated by each of three molecular sensors, including IRE1α, ATF6, and PERK. XBP1 undergoes unconventional splicing in the cytosol by IRE1α and is an obligate component in both IRE1α-induced (XBP1s) and ATF6-induced (XBP1u) arms of the UPR. IRE1α is the only ribonuclease known to date to splice XBP1.